Rheumatoid Arthritis: Risk Factors, Diagnosis, and Treatment

Joint erosion in RA is irreversible, therefore, early diagnosis and aggressive initial treatment are imperative.

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease that affects the joints, and lives, of more than 1.5 million Americans, or 1 in every 100. The lubricating synovium, which is the tissue that lines the joints, becomes inflamed and thickened when attacked by the immune system, so that painful swelling develops around the joints. This inflammatory process damages the cartilage and erodes the joint spaces between bones, leading to unstable, immobile, deformed, and painful joints.1 The joint destruction of RA is a cascading event, in which pannus, hyperplastic synovial tissue, and cartilage erosion result in subchondral bone, articular capsule, tendon, and ligament damage.2 The joint erosion is irreversible; therefore, early diagnosis and aggressive initial treatment are imperative.

This article discusses the most prevalent risk factors, as well as the clinical signs and symptoms, associated with RA. Current treatment modalities for and the prognosis of patients with RA are also discussed.

Epidemiology and etiology

RA is a chronic condition with no known specific cause; however, gender, heredity, genetics, and initiating factors are known risk determinants.3 RA is 3 times more likely to affect women than men. The peak age at onset in women is in the fourth to fifth decades; in men, the prevalence increases in the sixth to eighth decades. Although RA is not hereditary, certain genetic features can affect the risk for the development of this disease. Research indicates that the presence of rheumatoid factor (RF) in healthy individuals is of a greater significance than was initially understood, as the presence of both immunoglobulin M (IgM) and IgA RF is associated with a 7‐fold risk for seropositive RA.4 Moreover, it has been found that people with specific variants of the human leukocyte antigen (HLA) genes are at higher risk for the development of RA. Today, the best-known genetic risk factor for RA is inheritance of certain HLA-DRB1 alleles, which encode a “shared epitope” that is detected as a distinguishing 5-amino-acid sequence.5

Although the presence of the HLA-DRB1 alleles is not a specific indicator of disease, certain factors can enhance an individual’s susceptibility to the development of RA. These include infection, cigarette smoking, and stress, which are all very common in today’s society. Bacterial infections, primarily those involving the mouth and/or gut, are environmental factors hypothesized to increase the risk for RA.6 However, the most significant environmental risk factor for RA is smoking.7 In a Finnish population study, it was found that elevated RF levels were found twice as often in both current and former smokers as in nonsmokers; moreover, the proportion of smokers increased among those persons with higher RF titers.6 Other studies have also demonstrated an association between RF production and frequent cigarette smoking. Even if cigarette smoking is discontinued, once it has induced RF production, the process is irreversible.8 Stress can also exacerbate RA; research indicates that the onset of RA is often preceded by traumatic and/or stressful lifetime events.3 Furthermore, painful flare-ups of RA have been linked to exacerbations of stress. Stress management should be a critical component of the RA treatment plan, as living with a “painful, chronic, and somewhat unpredictable disease can be a significant source of stress in itself.”9

History and clinical presentation

Before the symptoms of RA become bothersome enough to cause someone to seek medical attention, early symptoms of RA, such as fatigue, muscle pain, low-grade fever, weight loss, and numbness and tingling in the hands, are often present.3 RA is described to have an “insidious” onset characterized by morning stiffness and a vague, prodromal pain in the affected joints. Morning stiffness characteristically lasts longer than 30 minutes.

RA presents most commonly as a symmetric polyarthritis affecting both small and large joints but particularly, the small joints of the hands and feet.5 The peripheral joints, especially the diarthrodial joints, are most commonly affected. The diarthrodial joints are lined with inflamed synovial membrane, and their bony surfaces are surrounded by hyaline cartilage. In RA, the diarthrodial joints most often involved are the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the fingers; the wrists, knees, and ankles; and the metatarsophalangeal (MTP) joints of the toes. The pathologic processes causing the red, inflamed, and dysmorphic joints observed on physical examination include synovial membrane proliferation, angiogenesis, endothelial cell activation, chemotactic stimuli, and the production of proinflammatory cytokines.6 The joint symptoms of RA typically are gradual in onset and include pain, stiffness, redness, warmth to the touch, and swelling. When the hands are assessed during physical examination, grip strength is often noted to be reduced.3

Two distinguishing features of long-standing RA are “swan neck” deformities and boutonniere deformities of the fingers (Figure 1).3 Swan neck deformities develop with hyperextension of the PIP joint and flexion of the distal interphalangeal (DIP) joint, whereas boutonniere deformities develop with flexion of the PIP joint and hyperextension of the DIP joint.12 A bowstring sign, which is the presence of prominent and tight tendons on the dorsum side of the hand, may also be evident on physical examination.

The wrist is the arm joint that is most commonly affected by RA. Difficulty bending the wrist backward is an early indicator of the disease, and movement requiring manipulation of the wrist is often arduous for patients with RA. Swelling of the elbow joint is also seen in RA; this can cause a tingling sensation running up the arm as a result of compression of the ulnar nerve. A limited range of motion in the shoulder may be noted on physical examination in the later stages of RA.

Swan neck deformities in the fingers of an elderly woman with rheumatoid arthritis.

In the lower extremities, the bases of the toes are commonly affected at the onset of RA. Having a patient stand on his or her toes will elicit pain; moreover, the plantar surface of the foot may appear swollen and erythematous. Swelling and difficulty flexing the knee may also be evident on examination. Baker’s cysts are frequently observed in patients with RA. In progressive and late cases, RA may involve the hips, causing walking to be both painful and difficult.

Although not extremely common, involvement of the cervical spine may cause inflammation between the shoulders and base of the head, resulting in a painful and stiff neck along with limited range of motion. Lastly, and perhaps most interestingly, the cricoarytenoid joint is involved in the RA process in 30% of patients. Because this joint is situated near the windpipe, the inflammation can cause difficulty breathing and hoarseness.3

Risks to articular structures in RA are tendon rupture and the formation of synovial cysts. Moreover, median nerve entrapment in the carpal tunnel is commonly seen. A distinguishing feature of RA is that although the disease can affect the neck, it does not involve other areas of the spine, as occurs in other forms of inflammatory arthritis. Another distinguishing examination finding is the presence of subcutaneous rheumatoid nodules, which are found in 20% of patients with RA. These nodules are most often seen over bony prominences; however, they can develop in the lungs, sclerae, and other tissues unrelated to joints. The RA nodules mirror the laboratory findings, as they are related to the presence of RF in serum.5

RA is more than a disease of the joints; it is known to cause problems in many other systems. Sjögren syndrome, characterized by dryness of the eyes, mouth, and mucous membranes, is observed in advanced RA. Scleral nodules can cause other ocular conditions, such as episcleritis, scleritis, and scleromalacia. Cough and progressive dyspnea on examination often indicate the presence of interstitial lung disease in patients with RA. Pericarditis and pleural disease are other comorbidities occasionally seen in RA. It is not uncommon to note mild vasculitis appearing as small hemorrhagic infarcts in the nail folds or finger pulp of patients with RA.4 The current criteria for a diagnosis of RA are presented in Table 1. A score higher than 6 in a possible total of 10 indicates an RA diagnosis.12

Laboratory workup

From 70% to 80% of patients with established RA have serologic titers of anti-cyclic citrullinated peptide (CCP) antibody and RF, which is an IgM antibody that antagonizes the Fc fragment of IgG. RF has a sensitivity of 50% for the detection of RA; anti-CCP antibodies are 95% specific for the disease, and anti-CCP measurement is therefore the most specific blood test for RA. Determining the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level in patients with suspected RA is also an integral component of the laboratory workup. The degree of elevation of both these markers tends to mirror the extent of RA pathology in the body.5

Antinuclear antibody (ANA) measurement, complete blood cell (CBC) count, platelet count, serum uric acid measurement, and HLA tissue testing aid in the differential diagnosis of RA and distinguish it from other arthritic and immunologic pathologies. Leukocytosis (white blood cell [WBC] count >11,000/μL) and thrombocytosis (platelet count ≥450 × 109/L) are commonly noted in the CBC count.13 Iron levels should be monitored because a moderate hypochromic normocytic anemia is commonly seen in RA. The joint fluid should be assessed to quantify inflammation and rule out gout or septic arthritis. Whereas osteoarthritic joint fluid typically appears yellow, RA joint fluid tends to be more yellow to opalescent, with a higher WBC count and platelet count than osteoarthritic joint fluid.2 Arthrocentesis is a needed diagnostic measure to rule out septic arthritis, a severe complication of RA. Clinicians should suspect septic arthritis when one joint is significantly more inflamed than other problematic joints.5

Radiographic changes are the most specific diagnostic measure for RA and are therefore of the utmost importance. Although little radiologic change is observed in the first 6 months after onset, initial changes are noted in the hands and feet as the soft tissue swells and juxta-articular demineralization occurs. As the disease progresses, decreased joint spaces and erosive processes become evident. The ulnar styloid and juxta-articular margins are the loci where bone erosion is often first identified on radiographs. Although magnetic resonance imaging and ultrasonography are more sensitive than radiography, the value of these modalities in the diagnosis of early RA has yet to be determined in comparison with plain film.5

Treatment options

If RA is suspected, the patient should promptly be referred to a rheumatologist for diagnosis, treatment initiation, and the development of a long-term strategy. Treatment should be initiated as soon as a diagnosis has been established to diminish pain, preserve joint function, and avoid future/further deformity. Besides pharmacologic treatment, the patient should be referred to physical and occupational therapy for holistic benefit.2

Disease-modifying antirheumatic drugs (DMARDs) are the established initial treatment for RA. This pharmacologic class has been shown to have a suppressive effect on disease activity. The DMARD of choice is methotrexate (MTX). Positive effects usually are noticed between the second and sixth weeks after treatment initiation. The initial prescribed dose is 7.5 mg, administered orally once weekly. If no notable difference occurs in the first month of MTX treatment, the dose can be increased to 15 mg once weekly; however, the dose should not exceed 20 to 25 mg/wk. Common MTX side effects include stomach irritation and gastritis. Patients with liver disease should not take MTX because it is known to cause hepatotoxicity with fibrosis and cirrhosis. MTX is a category X medication; therefore, women who are pregnant or wish to become pregnant are not candidates for this treatment option. Monitoring liver function as well as the WBC and platelet counts is an important aspect of prescribing MTX. Other prescribed DMARDs for the treatment of RA include sulfasalazine, leflunomide, antimalarial agents (hydroxychloroquine), minocycline, and tofacitinib.

In addition to these synthetic DMARDs mentioned above, biologic DMARDs are another treatment option for patients with RA. Drugs in this class include abatacept, rituximab, tocilizumab, and the tumor necrosis factor (TNF) inhibitors. TNF inhibitors are pro-inflammatory cytokines often administered to patients whose disease does not respond appropriately to MTX, or to patients with severe disease. The following TNF inhibitors are administered as subcutaneous injections: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. The ideal treatment regimen for patients with RA consists of a combination of MTX and a TNF inhibitor. It is well documented that a combination of the two drugs is superior to the use of either drug alone.5 For those who cannot tolerate TNF inhibitors, DMARD triple drug therapy, with MTX, sulfasalzine, and hydroychloroquine, has shown to be efficacious.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) relieve pain and reduce inflammation, they do not alter disease progression, nor do they serve to prevent erosive processes. Unfortunately, NSAIDs cannot be used as monotherapy or in conjunction with DMARDs, so their role in the treatment of RA is limited. Low-dose corticosteroids are another treatment option for patients with RA because they have been shown to prevent disease progression and to provide anti-inflammatory effects. Commonly, corticosteroids are used as an adjunct to DMARDs, reducing disease activity until the DMARDs have reached peak performance. However, corticosteroid treatment is of limited use in the long-term treatment of RA because prolonged steroid use is not advised. A taper should be implemented when corticosteroids are discontinued. If one or two joints are particularly bothersome to the patient, intra-articular corticosteroid injections are beneficial in offering symptomatic relief; however, the injections can be given only four times each year and therefore should be used sparingly.5

Prognosis

The outcomes of RA are variable and include remission, fluctuating disease, and progressively worsening disease. A well-documented study regarding the debilitation of RA indicates that 20% to 30% of patients diagnosed with the disease qualify for work disability 2 to 3 years from disease onset. In addition, 15 years from disease onset, 67% of patients are disabled.10 Complete disease remission has been documented but is rare. However, disease remission commonly occurs during pregnancy, though more than 90% of women experience increased arthritic symptoms 3 months postpartum.3 Early pharmacologic treatment greatly improves patients’ quality of life, because certain drugs can arrest joint damage and relieve the signs and symptoms of RA.5

If left untreated, RA can shorten life expectancy. So early, consistent treatment as the standard of care is essential. Studies indicate that the high mortality rates observed in patients with RA are due mainly to cardiovascular disease.5 The management of risk factors with smoking cessation, blood pressure control, a healthy diet, and stress management is paramount in decreasing the prevalence of cardiovascular disease in patients with RA.